Synthesis of Indenol- and Azulenol Derivatives via Platinum Dichloride-Catalyzed Intramolecular Hydroxy- or Alkoxycyclization of Cyclic Dienynes Ming-Chang P. Yeh,* Wen-Cheng Tsao, and Sau-Tin Cheng Department of Chemistry, National Taiwan Normal UniVersity, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan, Republic of China
[email protected] ReceiVed NoVember 11, 2007
Platinum dichloride-catalyzed hydroxy- or alkoxycyclization of cyclohexadienynes gives indenol derivatives, whereas hydroxy- or alkoxycyclization of cycloheptadienynes produces azulenol derivatives. The cyclization reaction proceeds via a cyclopropyl platinacarbene intermediate and allows for the direct stereocontrol of three contiguous stereogenic centers of the fused bicyclic skeletons. The transient reactive intermediate obtained from PtCl2-catalyzed cyclization reaction of a cyclohexadienyndiol can be trapped intramolecularly by a hydroxyl group to afford an oxatricyclo[5.4.0.04,8]undecane ring skeleton with extreme diastereoselectivity. The stereoselective construction of highly functionalized bicyclo[4.3.0] and -[5.3.0] building blocks is an important synthetic goal because such ring skeletons are present in numerous natural products of biological interest.1 Because the availability of functionalized bicyclo[4.3.0] and -[5.3.0] building blocks could greatly facilitate the elaboration of more complex target molecules, the design of expedient synthetic routes to such intermediates has been actively pursued.2 Recently, it has been shown that coordination of electrophilic PtCl2 to the alkyne group of enynes generates a (η2-alkyne)platinum complex, which evolves to form a cyclopropyl platinacarbene complex.3 Attack (1) (a) Shindo, K.; Kawai, H. J. Antibiot. 1992, 45, 292. (b) Shindo, K.; Matsuoka, M.; Kawai, H. J. Antibiot. 1996, 49, 241. (c) Shindo, K.; Iijima, H.; Kawai, H. J. Antibiot. 1996, 49, 244. (d) Shindo, K.; Sakakibara, M.; Kawai, H. J. Antibiot. 1996, 49, 249. (e) Molander, G. A. Acc. Chem. Res. 1998, 31, 603-609.
of nucleophiles (water or alcohols) at the transient reactive intermediate produced five- or six-membered carbo- or heterocyclic rings.4 We have now demonstrated that this methodology can be applied toward highly diastereoselective synthesis of indenol derivatives by treatment of cyclohexadienynes with water or an alcohol in the presence of 5 mol % of PtCl2, whereas hydroxy- or alkoxycylization of cycloheptadienynes using the same reaction condition afforded azulenol derivatives. The requisite cyclohexadienyne 1a was prepared by addition of sodium dimethylmalonate to the (η5-cyclohexadienyl)tricarbonyliron cation salt in THF according to literature procedures.5 Decomplexation of the resulting complex with cerium ammonium nitrate (CAN) in acetone at 0 °C afforded dimethyl 2-cyclohexa-2,4-dienylmalonate. Treatment of the malonate with sodium hydride followed by addition of propagyl bromide furnished 1a in 70% overall yield. Compound 1b was prepared in a similar fashion starting from 2,4-pentanedione and (η5-cyclohexadienyl)tricarbonyl-iron cation salt. The sevenmembered ring substrate 2 was prepared starting from addition of sodium dimethylmalonate to the (η5-cycloheptadienyl)tricarbonyliron cation salt following the same procedure as described above for synthesis of 1a. Our intramolecular hydroxycyclization of cyclic dienynes study began with 1a (Scheme 1). Addition of 5 mol % PtCl2 to 1a in refluxing H2O and acetone (1:1 mixture) for 18 h under nitrogen provided dimethyl 2,3,3a,4,7,7a-hexahydro-4-hydroxy-3-methyleneindene1,1-dicarboxylate (3a) in 72% isolated yield (Scheme 1). The product of the relative stereochemistry as depicted was obtained as a single diastereomer, which is derived from an anti addition of the alkyne and H2O across the proximal double bond of the conjugated diene. The relative stereochemistry of 3a was determined as 1,2-trans, 2,3-cis relationship on the basis of NOSEY (nuclear Overhauser enhancement spectroscopy) measurements. Three contiguous stereogenic centers are created with extreme diastereoselectivity. In general, cis-fused hexahydroindene skeletons are constructed via intramolecular Diels-Alder reaction conditions. However, the Diels-Alder reaction required heating substrates at elevated temperature in toluene in a sealed (2) For bicyclo[4.3.0]compounds see: (a) Gassman, P. G.; Gorman, D. B. J. Am. Chem. Soc. 1990, 112, 8623. (b) Gassman, P. G.; Gorman, D. B. J. Am. Chem. Soc. 1990, 112, 8624. (c) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc. 1990, 112, 4965. For bicyclo[5.3.0]compounds see: (d) Kusama, H.; Onizawa, Y.; Iwasawa, N. J. Am. Chem. Soc. 2006, 128, 16500. (e) Ni, Y.; Montgomery, J. J. Am. Chem. Soc. 2006, 128, 2609. (f) Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624. (g) Harvey, D. F.; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 5066. (3) (a) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996, 15, 901. (b) Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. (c) Me´ndez, M.; Mamane, V.; Fu¨rstner, A. ChemTracts-Org. Chem. 2003, 16, 397. (d) Mamane, V.; Gress, T.; Jrause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (4) (a) Martı´n-Matute, B.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003, 125, 5757. (b) Me´ndez, M.; Paz Mun˜oz, M.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511. (c) Martı´n-Matute, B.; Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2001, 40, 4754. (d) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813. (e) Me´ndez, M.; Echavarren, A. M. Eur. J. Org. Chem. 2002, 15. (5) (a) Yeh, M. C. P.; Sheu, B. A.; Fu, H. W.; Tau, S. I.; Chuang, L. W. J. Am. Chem. Soc. 1993, 115, 5941. (b) Yeh, M. C. P.; Sun, M. L.; Lin, S. K. Tetrahedron Lett. 1991, 32, 113. (c) Yeh, M. C. P.; Tsao, W. C.; Ho, J. S.; Tai, C. C.; Chiou, D. Y.; Tu, L. H. Organomteallics 2004, 23, 792. 10.1021/jo702424w CCC: $40.75 © 2008 American Chemical Society
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Published on Web 03/11/2008
SCHEME 1. PtCl2-Catalyzed Indenol Derivatives Synthesis from Cyclohexadienynes
tube.6 The current approach to the synthesis of cis-fused hexahydroindenes is achieved without the use of complex catalysts or critical reaction conditions, only requiring platinum dichloride and alcohols or water. The reaction pathway leading to indenol 3a was suggested as follows. The catalyst coordinated to the triple bond of 1a to give 4a (Figure 1), which was then attacked by the proximal double bond of diene. This generated intermediate 4b with the newly formed carbon-carbon bond. The 2,3-cis relative stereochemistry of the ring juncture of 4b was fixed by the alkyne moiety aligned to the face of the cyclic diene in which the tethering chain resides. Intermediate 4b led to the cyclopropyl platinacarbene intermediate 4c as suggested in the literature.4 The postulated intermediate 4c was then attacked by H2O at the allylic carbon from the convex face to give the bicyclic skeleton 5 containing an η1-alkenylplatinum bond. Protonation of 5 at the metal center followed by reductive elimination led to 3a and regenerated PtCl2 catalyst into the catalytic cycle. The postulated mechanism was previously proposed for platinum- and gold-catalyzed cycloisomerization reactions of enynes.3d
SCHEME 2. PtCl2-Catalyzed Azulenol Deivatives Synthesis from Cycloheptadienynes
To explore the scope of oxygen nucleophiles, a variety of alcohols were examined under the same reaction conditions. Results of alkoxycyclization of dienynes 1a with 5 mol % of PtCl2 catalyst in various alcohols are listed in Scheme 1. Methanol, allylic alcohol, and isopropyl alcohol were efficient nucleophilic solvents as the yields of desired alkoxycyclization products 3b-d ranged from 55 to 74%. However, indenols
formation failed to occur for 1a in the presence of benzylic alcohols. For example, treatment of 1a with 5 mol % of PtCl2 using 4-methylbenzyl alcohol or naphthalen-1-ylmethanol as nucleophilic solvents failed to give cyclized products and the reactions led to unidentified mixtures in each case. The reactive benzylic alcohols could add at the Pt-alkyne carbon of the transient intermediate 4a or various electrophilic sites of 4b and 4c and gave a mixture of unidentified compounds. Furthermore, PtCl2-catalyzed isopropoxylation of the diketo substituted dienyne 1b produced the desired indenol derivative 3e in 40% yield (Scheme 1). The relative stereochemistry of 3a-e were assigned as the same 1,2-trans, 2,3--cis relationship on the basis of their close chemical shift values and similar coupling patterns of the protons at the C-2 position in their 1H NMR spectra. Increasing the ring size by one with cyclohepta-1,3-dienynes 2a-e (Scheme 2) also underwent hydroxy- or alkoxycyclization to afford azulenol derivatives 6a-e, respectively, as the only stereoisomer in each case. 1H NMR studies provided the initial evidence for support of the structure assignments. The hydrogen shift (δ) of 2.94 in 6a exhibited as a triplet was assigned to H2. The coupling constant of H1-H2 (J12) of 9.0 Hz agrees with the 9-10 Hz coupling constant for the similar trans hydrogens found in the literature.7 Furthermore, the coupling constant of H2-H3 (J23) of 9.0 Hz agrees with the 9-10 Hz coupling constant for similar cis hydrogens compared to the 11-12 Hz observed when these protons are trans.7 The relative stereochemistry of 6a-e were assigned as the same 1,2-trans, 2,3cis relationship on the basis of their close chemical shift values and similar coupling patterns of the proton at the C-2 position in their 1H NMR spectra. The structure elucidation of 6b and 6c were finally accomplished by X-ray diffraction analysis. The 1,2-trans, 2,3-cis relative stereochemistry of 6a-e, derived from an anti addition of the alkyne and H2O or an alcohol across the proximal double bond of the conjugated diene, further supports the proposed reaction path suggested for the formation of indenols 3a-e (Figure 1). Using the same reaction conditions, we were able to construct an oxatricyclo[5.4.0.04,8]undecane ring skeleton, such as 7, by intramolecular addition of a hydroxyl group to a postulated reactive cyclopropyl platinacarbene intermediate. Thus, treatment of dienyndiol 8, obtained by addition of 2.5 molar equiv of diisobutylaluminum hydride to 1a followed by acid quenching, with 5 mol % PtCl2 in toluene at 80 °C for 16 h furnished
(6) (a) Chang, J.; Paquette, L. A. Org. Lett. 2002, 4, 253. (b) Munakata, R.; Ueki, T.; Katakai, H.; Takao, K.; Tadano, K. Org. Lett. 2001, 3, 3029. (b) Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043.
(7) (a) Yeh, M. C. P.; Jou, C. F.; Yeh, W. J.; Chiu, D. Y.; Reddy, N. R. K. Tetrahedron 2005, 61, 493. (b) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006, 128, 6931.
FIGURE 1. Reactive Intermediates 4a-c and 5.
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SCHEME 3. PtCl2-Catalyzed Synthesis of Oxatri-cyclo [5.4.0.04,8]undecane Skeleton 7 from Cyclohexa-dienyndiol 8
allylic substitutions.11 Therefore, the resulting indenol- and azulenol derivatives containing an allylic alcohol or ether would be expected to demonstrate still higher levels of synthetic utility. Experimental Section
the heterotricyclic compound 7 in 51% isolated yield (Scheme 3). NOSEY (nuclear Overhauser enhancement spectroscopy) experiments provided the initial evidence for support of all syn relationships among hydrogen atoms at C-1, C-2, and C-3 of 7. The formation of 7 was suggested in Scheme 2. Coordination of the alkyne of 8 to the Pt metal center followed by intramolecular nucleophilic addition of the diene to the Pt-alkyne moiety generated the reactive cyclopropyl platinacarbene intermediate 9. Due to two fused protons presented on the convex face, the endo hydroxyl group would attack at the cyclopropyl ring from the concave face followed by protonation/reductive elimination of the Pt metal center to afford the oxatricycle 10, which then underwent double bond migration to furnish 7. In summary, a platinum dichloride-catalyzed hydroxy- or alkoxycyclization of dienynes has been successfully developed. The conjugated diene added to the alkyne in the presence of a catalytic amount of PtCl2 and H2O or an alcohol to afford indenol or azulenol derivatives. Under the same reaction conditions, intramolecular hydroxycyclization of a cyclohexadienyndiol generated an oxatricyclo[5.4.0.04,8]undecane ring skeleton. Due to their numerous reactivities, allylic alcohols and ethers are versatile substrates in a variety of organic transformations including Claisen rearrangements and related processes,8 epoxidations,9 cyclopropanations,10 and palladium-catalyzed (8) (a) Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026.(b) Donde, Y.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 2933. (c) Metz, P.; Hungerhoff, B. J. Org. Chem. 1997, 62, 4442. (9) Johnson, R. A.; Sharpless, K. B. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 7, p 389. (10) (a) Denmark, S. E.; O’Connor, S. J. Org. Chem. 1997, 62, (584). (b) Charette, A. B.; Marcoux, J. F. Synlett 1995, 1197.
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General Procedure for Platinum Dichloride-Catalyzed Intramolecular Hydroxy- or Alkoxycyclization of Cyclic Dienynes. Cyclic dienyne (1.0 mmol) and PtCl2 (0.05 mmol) were mixed in refluxing H2O/acetone (1:1, 30 mL) or an alcohol (30 mL) until all dienyne was consumed (typically 16 h). The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3 × 50 mL). The organic phase was dried (MgSO4), filtered, and concentrated to give the crude mixture. (()-(3aS,4R,7aR)-Dimethyl 2,3,3a,4,7,7a-Hexahydro-4-hydroxy3-methyleneindene-1,1-dicarboxylate (3a). The crude mixture from intramolecular hydroxycyclization of 1a (0.25 g, 1.0 mmol) was purified by flash column chromatography12 (silica gel, 10% ethyl acetate/hexanes) to give 3a (0.19 g, 0.72 mmol, 72%) as a pale-yellow oil: 1H NMR (500 MHz, CDCl3) δ 5.82 (m, 1H), 5.74 (m, 1H), 4.97 (d, J ) 1.9 Hz, 1H), 4.90 (d, J ) 2.0 Hz, 1H), 4.19 (brs, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.28 (dd, J ) 17.9, 1.4 Hz, 1H), 3.03 (m, 1H), 2.86 (m, 2H), 2.00 (dt, J ) 17.9, 5.8 Hz, 1H), 1.86 (m, 1H), 1.72 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 171.9, 170.4, 147.4, 127.8, 127.6, 106.9, 65.0, 61.5, 52.8, 52.7, 49.8, 38.8, 38.0, 22.9; IR (CH2Cl2) 3554, 2918, 2750, 1710, 1515, 1443, 1372, 1007 cm-1; MS (EI) m/e 266.3 (M+, 0.3), 197.2 (63), 188.2 (28), 165.2 (43), 145.2 (34), 137.2 (100), 129.2 (64), 128.1 (39), 91.1 (51), 77.1 (62), HRMS (EI) m/e calcd for C14H18O5 266.1154, found 266.1153. (()-(3aS,4R,8aR)-Dimethyl 2,3,3a,4,8,8a-Hexahydro-4-methoxy-3-methyleneazulene-1,1(7H)-dicarboxylate (6b). The crude mixture from intramolecular hydroxycyclization of 2 (0.262 g, 1.0 mmol) was purified by flash column chromatography7 (silica gel, 5% ethyl acetate/hexanes) to give 6b (0.191 g, 0.65 mmol, 65%) as a pale-yellow powder: mp 41-43 °C; 1H NMR (400 MHz, CDCl3) δ 5.58 (m, 1H), 5.56 (m, 1H), 5.12 (brs, 1H), 4.96 (brs, 1H), 4.04 (brd, J ) 8.9 Hz, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 3.33 (s, 3H), 3.19 (dd, J ) 17.0, 2.4 Hz, 1H), 3.08 (ddd, J ) 9.5, 7.5, 2.1 Hz, 1H), 3.00 (m, 1H), 2.84 (dd, J ) 17.0, 1.0 Hz, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 1.51 (qd, J ) 14.0, 4.6 Hz, 1H), 1.33 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 171.7, 170.6, 148.6, 132.2, 129.0, 109.2, 79.1, 63.3, 56.7, 52.7, 52.4, 51.8, 45.5, 39.6, 29.0, 24.1; IR (CH2Cl2) : 3475, 3020, 295 3, 2820, 2073, 1733, 1654, 1435, 1396, 1264, 1156 cm-1; MS (EI) m/e (rel intensity) 294.3 (M+, 8), 234.2 (84), 202.2 (85), 187.2 (10), 170.1 (54), 143.1 (79), 128.1 (44), 117.1 (28), 105.1 (20), 91.1 (100); HRMS (EI) m/e calcd for C16H22O5 294.1467, found 294.1462. Crystals suitable for X-ray diffraction analysis were grown from CH2Cl2 and hexanes.
Acknowledgment. This work was supported by grants from the National Science Council (NSC 95-2113-M-003-003). Supporting Information Available: 1H NMR and 13C NMR spectra of compounds 3b-e, 6a, and 6c-e and X-ray crystallographic information files for compounds 6b and 6c. This material is available free of charge via the Internet at http://pubs.acs.org. JO702424W (11) Trost, B. M.; VanVranken, D. L. Chem. ReV. 1996, 96, 395. (12) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
